Earlier R&D Programs, Maturing Candidates Emerge From Bristol’s Pipeline
Mid-Stage Milvexian Cleared First Proof-Of-Concept Hurdle
Executive Summary
BMS is advancing a growing Phase I and II R&D pipeline, including a Factor XIa inhibitor with lower bleeding risk than current anticoagulants, as well as other internal and external research programs.
Bristol Myers Squibb Company is under pressure to bring new drugs to market before several of its current blockbuster products face generic and biosimilar competition. But in addition to a suite of late-stage and newly approved therapies that it believes will generate more than $25bn in new revenue by 2029, the company has a rapidly growing pipeline of Phase I and II research and development programs with many drug candidates on the cusp of proof-of-concept data or nearing advancement into Phase III.
Bristol showcased some of its early and mid-stage clinical programs that may help BMS grow its revenue base later in this decade and beyond during an investor event on 16 November. Scrip also spoke with Samit Hirawat, chief medical officer and executive vice president of global drug development, as well as Rupert Vessey, EVP and president of early research and development, about the company’s pipeline building strategies and its focus on successful execution of R&D programs.
“Overall, when we think about the execution over the last year, we have really improved our ability to focus on what is important – despite the pandemic, how to work collaboratively internally and externally; how to utilize the best resources that we have available in terms of the people that we have; how to ensure that our acceleration continues on in terms of the urgency for the indications that we are pursuing,” Hirawat said.
He noted, for instance, that BMS learned a lot during the COVID-19 pandemic about how to execute clinical trials more efficiently for the company and for its trial participants, including through the use of digital technologies and decentralized trial strategies.
In terms of clinical trial success, Vessey emphasized the role of his early R&D group in determining which drug candidates to move into clinical development and to advance into later-stage trials. That includes investing heavily in translational research, moving programs forward in preclinical development against drug targets that have been genetically validated, and using computational methods to select the appropriate patient populations for clinical testing, all to increase chances for success in human trials.
“We incentivize our workforce at the corporate level to make decisions on data rather than simply to advance things up the pipeline, which is different from other places that I've worked,” Vessey said.
Moving Past Proof-Of-Concept: Milvexian In The Spotlight
The BMS clinical development pipeline is largely focused on four key therapeutic areas – oncology, hematology, cardiology and immunology – but the company is also taking a thoughtful approach to neurology drug development through both internal research and external collaborations.
R&D Pipeline Statistics
Since 2019, Bristol’s pipeline has grown from 29 Phase I and II assets to 64 and from 11 to 22 Phase III and registrational expansion opportunities. The company plans to review proof-of-concept data and determine which assets to move into later-stage development for more than 20 programs during the next three years.
BMS has more than 300 external partnerships. The early research and development group alone has more than 85 active collaborations with nine licenses executed so far in 2021 and four investigational new drug (IND) applications filed this year.
Cardiology has become an increasing important therapeutic area through Bristol’s ongoing partnership with Janssen Pharmaceutical Cos., which yielded the blockbuster anticoagulant Eliquis (apixaban), and through the company’s $13.1bn acquisition of MyoKardia, Inc. last year that gave BMS the allosteric myosin inhibitor mavacamten for hypertrophic cardiomyopathy (HCM), a product that is expected to deliver more than $4bn in revenue by 2029. A US Food and Drug Administration approval decision on mavacamten’s first indication in obstructive HCM is expected by 28 January. (Also see "BMS Buys MyoKardia, Plans To Use Eliquis Experience To Grow Mavacamten" - Scrip, 5 Oct, 2020.)
And data presented on 15 November at the American Heart Association (AHA) annual meeting revealed promising Phase II results for another anticoagulant, the Factor XIa inhibitor milvexian, also partnered with Johnson & Johnson’s Janssen subsidiary.
Bristol has a long history in big cardiovascular disease franchises, including the Factor Xa inhibitor Eliquis, which fffffffffdelivered $9.2bn in 2020 revenue and the anti-platelet drug Plavix (clopidogrel), which delivered peak sales of $7.1bn in 2011 before it faced generic competition. With Eliquis slated to lose patent protection during the latter half of the 2020s, the pressure is on for BMS to extend its anti-thrombotic franchise.
The milvexian data presented during the AHA meeting came from the Phase II AXIOMATIC-TKR study evaluating the safety and efficacy of the oral drug versus Lovenox (enoxaparin) for 10-14 days in patients undergoing elective total knee replacement surgery. The clinical trial enrolled 1,242 who were randomized to one of seven once- or twice-daily doses of milvexian or a daily subcutaneous enoxaparin injection. The primary efficacy endpoint was the incidence of total venous thromboembolism (VTE) at up to day 14. The primary safety endpoints was any bleeding, defined as the composite of major, clinically relevant non-major and minimal bleeding.
Milvexian reduced the incidence of VTE in a dose-dependent manor with just 8% of patients treated with a twice-daily 200mg dose and 7% treated with a once-daily 200mg dose experiencing VTE compared with 21% of patients treated with a daily 40mg injection of enoxaparin.
There were no major bleeding events among milvexian-treated patients, but there was one in the enoxaparin arm of the study. Rates of any bleeding event for milvexian were 3% in the twice-daily 200mg group and 6% in the once-daily 200mg group compared with 4% for enoxaparin, while only 1% of patients in the two highest-dose milvexian groups had a major or clinically relevant non-major bleeding event compared with 2% in the comparator arm.
BMS described these results as distinct from existing anticoagulants, use of which is limited by cardiologists’ concerns about increased bleeding events.
William Blair analyst Matt Phipps shared insights about milvexian’s potential in a 17 November note that cited comments from Jeffrey Berger, director of NYU Langone Health’s Center for the Prevention of Cardiovascular Disease. Berger “was very encouraged” by the AXIOMATIC-TKR results, Phipps said, noting that the cardiologist was unwilling to declare Factor XIa inhibition to be de-risked in the absence of Phase III data.
“He highlighted the experience with PAR1 inhibitors, such as vorapaxar, which showed initial promise before clinical trials were halted due to increased risk of brain bleeding,” the analyst said.
Bristol and Janssen will review the results from AXIOMATIC-TKR and an ongoing Phase II secondary stroke prevention (SSP) trial to determine the Phase III path forward for milvexian. The AXIOMATIC-SSP study is testing milvexian in combination with clopidogrel and aspirin versus clopidogrel and aspirin alone in 2,350 patients following acute ischemic stroke or transient ischemic attack with a readout anticipated during the first half of 2022.
Milvexian, with its reduced rate of major bleeding events, could be developed across the SSP, acute coronary syndrome, coronary artery disease and peripheral artery disease indications covered by anti-platelet therapies as well as the VTE and atrial fibrillation indications covered by Factor Xa inhibitors, depending on the safety and efficacy outcomes in Phase II studies. BMS expects milvexian to move into Phase III as early as the second half of 2022.
Optionality In Cardiology: Milvexian, Mavacamten And Beyond
“With milvexian, we have the optionality of a multitude of indications once the secondary stroke prevention study reads out and we have the data to support single agent as well as combination strategies with anti-platelet agents,” Hirawat said.
He noted that the MyoKardia acquisition also gave BMS several early-stage heart disease drug candidates, some in Phase I right now, “so as that data evolves, that would be very helpful in obviously continuing our vision towards creating more therapeutics in the cardiovascular and heart failure space as well.”
Vessey said BMS is benefitting from MyoKardia’s “very good research team that were working on a range of things in discovery – other genetic forms of cardiomyopathy with different kinds of drug targets in the heart muscle, a lot of genetically defined diseases – and they built a really nice set of tools for validating targets and for testing drugs against those targets.” That team has been integrated into Bristol’s existing cardiovascular research group.
“We will continue to mine that [MyoKardia] portfolio for new opportunities and then we continue to look around,” Vessey said. He noted that BMS has “a small gene therapy effort in the cardiovascular space” through a collaboration it initiated with uniQure NV in 2015 “and we've been monitoring a few of the newer companies that are working in the cardiac gene therapy space as well to see if we think there's an opportunity there.” (Also see "BMS dives whole-heartedly into gene therapy with uniQure" - Scrip, 6 Apr, 2015.)
Early Neuroscience Research At BMS Via Celgene
Partners in neuroscience R&D include Dragonfly Therapeutics, Inc. in the areas of multiple sclerosis and neuroinflammation, Skyhawk Therapeutics, Inc. with a focus on RNA splicing opportunities, and Abide Therapeutics Inc. (acquired by H. Lundbeck A/S in 2019) with an endocannabinoid enhancer in early clinical development. Many of Bristol’s neurology efforts came in to the company through its $74bn acquisition of Celgene Corporation two years ago.
“When we started this effort, we were looking at adjacencies to some of the sort of pathophysiology that we were really good at researching –inflammation and immunology,” said Vessey, who also came to BMS from Celgene.
“We know from the genetics of neurodegenerative disease that there's a really important path for the inflammatory system in those diseases, and also in aberrant protein expression or protein homeostasis,” he continued. “And so, when we originally started, we wanted to use our protein degradation platform to see if there were things that we could identify, mostly in the phenotypic screens, that would allow us to bring forward novel therapies for neurodegenerative disease.”
As part of its protein degradation research in neurodegeneration, Bristol is working with Evotec SE. which has a proprietary platform of induced pluripotent stem cells (iPSCs) derived from patients with genetically defined neurodegenerative disorders. BMS and Evotec continue to identify and validate findings from that research, but the big pharma recently in-licensed its first compound from that effort.
Altogether, Bristol has three neuroscience programs in clinical development with another two moving into the clinic during the next few months. By 2023, the company will have taken five programs through Phase I.
“Our focus really has been on neurodegeneration and in many cases on fairly well-defined subsets of patients with neurodegeneration,” Vessey said. “So we're trying to look at … pretty homogeneous patient populations to maximize our chances of seeing a signal; we have a heavily biomarker-driven approach to development. We've got a strong imaging group at BMS that can do PET imaging and other types of imaging and that's a cornerstone of advancing the compounds and trying to demonstrate that they've got activity wherever that's appropriate.”
BMS is getting to the point where it will decide how to advance its early clinical-stage neuroscience programs into later stages of development and in which indications.
“That's something we're actively working on within the company at the current time, but we're very encouraged by the success that we've had to date,” Vessey said. “And we like the fact that we've done this in a novel way without having to establish a large internal footprint to date, and we think this will give BMS an option to be in another space at a time when we think there are real advances in this field.”
He noted that across Bristol’s R&D pipeline, the company intends to derive about a third of its drug candidates from its network of collaborators.